Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004134 (ataxia)
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The antagonism of various components of maximal Metrazol-seizures (MMS) (i.e. tonic hindpaw extension, tonic backward extension of the forepaws, generalized clonic seizures and tremors), ataxia and loss of righting reflex-activity have been studied in a standardized procedure comparing 41 antiepileptics and related compounds. Appropriate analyses (Cluster Analysis and Principal Component Analysis) resulted in the distinction of seven clusters which could be considered along two continua. A first continuum is characterized by a progressive strengthening of loss of righting reflex-inducing properties, a decreasing dissociation of ataxia and loss of righting reflex and the disappearance of a selective anticonvulsant effect. The second continuum is characterized by an increasing relative potency of ataxia-inducing properties, an increasing dissociation of ataxia and loss of righting reflex and a decreasing antagonism of tremors. Three main types of anticonvulsants could be defined: drugs with a complete anti-MMS effect antagonizing both clonic and tonic seizures; drugs selectively abolishing tonic seizures, i.e., tonic extension of hind- and forepaws; and drugs exclusively blocking tonic hind-paw extension. The neurological and clinical significance of these different types of anticonvulsant activity has been discussed. Finally, the described modification of the maximal Metrazol-seizures test is proposed for routine screening purposes.
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PMID:Antagonism of maximal metrazol seizures in rats and its relevance to an experimental classification of antiepileptic drugs. 103 60

MK-801 is a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist with anticonvulsant and neuroprotective properties. The action of MK-801 (0.05-10 mg/kg IP) was assessed against pentylenetetrazol-induced seizures (PTZ; 100 mg/kg SC; 30 min after MK-801) in rats aged 7, 12, 18, 25, and 90 days (N = 263). We observed pronounced ataxia and hypermobility after MK-801 pretreatment during the whole ontogenesis, and the animals exhibited head-weaving and body-rolls. After the combination of MK-801 and PTZ "wet dog shakes" were detected in 18-, 25-, and 90-day-old rats (never seen in controls receiving PTZ only). MK-801 only insignificantly modified the latencies of minimal (clonic) seizures in 18-day-old and older rats where this seizure type is regularly elicited. In 12-day-old rats an increased incidence of minimal seizures was detected. MK-801 nearly completely blocked or strongly delayed major (generalized tonic-clonic) seizures and attenuated the seizure severity during ontogenesis in a dose-dependent manner. Present results suggest the important role of NMDA receptors in the genesis of generalized tonic-clonic seizures whilst the role of NMDA receptors in minimal seizures appears to be negligible during the whole ontogenetic development.
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PMID:Excitatory amino acid antagonists and pentylenetetrazol-induced seizures during ontogenesis. II. The effects of MK-801. 183 2

The records of 483 patients admitted to the emergency room because of syncope were reviewed. Thirty seven patients (7.7%) were found to suffer from transient ischemic attack- (TIA) related syncope. This group is the subject of this report. Of these patients, 28 (76%) were men (mean age 71 years). Seven patients reported previous syncopal episodes. Past history revealed a high rate of ischemic heart disease (70%) and hypertension (68%). Concurrent neurologic symptoms, which led to the diagnosis of TIA-related syncope, included mainly vertebrobasilar symptoms: vertigo (in 55% of the patients), ataxia (46%), parasthesia (41%). Two patients most probably were presenting bilateral carotid artery disease. Various diagnostic tests (including electroencephalography, computed tomography, sonography, and cerebral angiography) were used to exclude other causes of syncope. During follow-up (mean 14.5 months) four patients (11%) had an additional episode of TIA and in three of them syncope reappeared. One patient had a complete stroke. We conclude that TIA is a much more frequent explanation for syncope than has been previously argued. These patients tend to be elderly males with high incidence of ischemic heart disease and hypertension. The concurrent neurologic symptoms, leading to the diagnosis, represent mainly vertebrobasilar territory ischemia.
Clin Cardiol 1991 Feb
PMID:Transient ischemic attack-related syncope. 204 43

Three male children with Friedreich's ataxia, from a single family, are described. The first patient presented as a cardiologic problem with anginalike chest pain. He was found to have echocardiographic evidence of concentric left ventricular hypertrophy (LVH). He later developed ataxia. The younger brother also had LVH but was asymptomatic and later became ataxic. The elder brother was already ataxic at the time of diagnosis. To our knowledge this is the first report of echocardiographic concentric left ventricular hypertrophy preceding the neurologic syndrome of Friedreich's ataxia.
Pediatr Cardiol 1985
PMID:Friedreich's ataxia presenting as cardiac disease. 404 Feb 39

Amiodarone was administered to 154 patients who had sustained, symptomatic ventricular tachycardia (VT) (n = 118) or a cardiac arrest (n = 36) and who were refractory to conventional antiarrhythmic drugs. The loading dose was 800 mg/day for 6 weeks and the maintenance dose was 600 mg/day. Sixty-nine percent of patients continued treatment with amiodarone and had no recurrence of symptomatic VT or ventricular fibrillation (VF) over a follow-up of 6 to 52 months (mean +/- standard deviation 14.2 +/- 8.2). Six percent of the patients had a nonfatal recurrence of VT and were successfully managed by continuing amiodarone at a higher dose or by the addition of a conventional antiarrhythmic drug. One or more adverse drug reactions occurred in 51% of patients. Adverse effects forced a reduction in the dose of amiodarone in 41% and discontinuation of amiodarone in 10% of patients. The most common symptomatic adverse reactions were tremor or ataxia (35%), nausea and anorexia (8%), visual halos or blurring (6%), thyroid function abnormalities (6%) and pulmonary interstitial infiltrates (5%). Although large-dose amiodarone is highly effective in the long-term treatment of VT or VF refractory to conventional antiarrhythmic drugs, it causes significant toxicity in approximately 50% of patients. However, when the dose is adjusted based on clinical response or the development of adverse effects, 75% of patients with VT or VF can be successfully managed with amiodarone.
Am J Cardiol 1983 Nov 01
PMID:Long-term efficacy and toxicity of high-dose amiodarone therapy for ventricular tachycardia or ventricular fibrillation. 663 51

Amiodarone was used to treat cardiac arrhythmias that had been refractory to conventional medical therapy. The first 70 consecutive patients treated with amiodarone in this study had at least 6 months of follow-up (range 6 to 24, mean 11) and form the basis for this report. Sixty-six patients were treated for ventricular arrhythmias and four for supraventricular tachycardias. Amiodarone therapy consisted of a loading dose of 600 mg orally twice a day for 7 days, and 600 mg daily thereafter. Doses were reduced only if side effects occurred. Because of frequent side effects, the dose was reduced from 572 +/- 283 mg per day (mean +/- standard deviation) at 45 days to 372 +/- 174 mg per day at 6 months. With a mean follow-up of 11 months in the 54 patients who continued to take amiodarone, only 4 patients had ventricular fibrillation. Three additional patients experienced recurrent sustained ventricular tachycardia in long-term follow-up. All 70 patients had extensive clinical and laboratory evaluation in follow-up. Side effects were common, occurring in 93% of patients. Thirteen patients (19%) had to discontinue the medication because of severe side effects. Fifty-six patients had gastrointestinal side effects, most commonly constipation. All patients but 1 eventually developed corneal microdeposits, and 43 patients were symptomatic. Cardiovascular side effects were uncommon. Symptomatic pulmonary side effects occurred in seven patients, with unequivocal pulmonary toxicity occurring in five. Neurologic side effects, most commonly tremor and ataxia, occurred in 52 patients. Thyroid dysfunction occurred in 3 patients, and 32 patients had cutaneous abnormalities. Miscellaneous other side effects occurred in 32 patients. Amiodarone appears to be useful in the management of refractory arrhythmias. Because virtually all patients develop side effects when given a maintenance daily dose of 600 mg, lower maintenance doses should be used. It is unknown if the more severe side effects are dose-related. Amiodarone is difficult to administer because of its narrow toxic-therapeutic range and prolonged loading phase. More importantly, the first sign of antiarrhythmic failure may be manifest as sudden cardiac death.
J Am Coll Cardiol 1983 Dec
PMID:Toxic and therapeutic effects of amiodarone in the treatment of cardiac arrhythmias. 668 51

The clinical effectiveness of flecainide acetate was evaluated in 36 patients (29 male and 7 female, average age 56 years) in whom therapy with previous antiarrhythmic agents had failed. All patients had documented ventricular tachycardia on Holter electrocardiographic recording and 31 of 36 (86%) had had syncope or required cardiopulmonary resuscitation, or both. Angiographic findings demonstrated significant coronary artery disease in 22 (61%) and primary left ventricular dysfunction in 14 (39%), with a left ventricular ejection of 0.39 +/- 0.4. Patients were treated with an average flecainide dose of 302 +/- 76 mg/day. The follow-up time was 101 +/- 156 days. Thirty-two of 36 patients (89%) had complete elimination of ventricular tachycardia from Holter monitoring and only 2 patients had flecainide discontinued because of noncardiac side effects (numbness, blurred vision and ataxia). However, the drug was subsequently discontinued in 5 patients because of cardiac side effects (proarrhythmic effect in 2, sinus bradycardia in 1, complete atrioventricular block in 1 and new left bundle branch block in 1) and 10 patients died during flecainide therapy (1 with cerebral stroke, 3 with congestive heart failure and 6 with incessant ventricular tachycardia). A comparison of the general cardiac features of those who died with those who did not revealed a significantly lower ejection fraction (0.24 +/- 0.1 vs 0.45 +/- 0.1, p less than 0.05) and a significantly higher flecainide dose (350 +/- 85 versus 276 +/- 59 mg/day, p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
Am J Cardiol 1984 Feb 27
PMID:Evaluation of flecainide acetate in the management of patients at high risk of sudden cardiac death. 669 14

A female patient, who died at the age of 61 and had suffered from several manic-depressive psychoses for more than 30 years, developed three phases of intoxication under lithium therapy. There was a 15-year history of electro- and Pentetrazol-induced convulsive therapy prior to lithium medication; neuroleptics were still administered during lithium therapy. The last lithium intoxication, 3 years prior to death was during a low-dosage therapy with normal lithium levels followed by severe lasting impairment: akinesia, rigidity, dysarthria, ataxia, and an organic alteration in character. For the first time, neuropathological findings could be established in such a case: extensive damage to granule and Purkinje cells in the cerebellum; gliosis in the dentate nucleus, the inferior olives, and the nucleus ruber; cytoplasmic inclusions in various nerve cells of the cranial nerve nuclei; cytoplasmic vacuoles, especially in the cells of the supra-optic nucleus. Surprisingly little damage could be found in the substantia nigra and in the neostriatum. The clinical course as well as the pattern and intensity of the brain damage oppose an interpretation as a consequence of preceding convulsive shock therapy.
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PMID:Clinical and neuropathological aspects of long-term damage to the central nervous system after lithium medication. 679 83

Pentylenetetrazol (PTZ) and sodium valproate (VPA) produce acutely in the naive rat various behavioural effects resembling signs of opiate withdrawal in the morphine-treated subject. Suggestions in the literature that these substances may activate directly some of the neural consequences of opiate and drug withdrawal prompted us to look for and examine possible aversive effects of these substances at non-toxic doses. With a sensitive two-flavour, three-trial taste aversion procedure, relatively low doses of PTZ and VPA (5 and 160 mg/kg, respectively) do indeed have aversive effects. The maximum aversions were produced by 10 and 20 mg/kg PTZ and 320 mg/kg VPA and were equivalent to those of morphine withdrawal precipitated by 0.01-0.03 mg/kg naloxone in a morphine pellet-implanted animal. Moreover, the maximum aversions with PTZ and VPA were significantly higher than the maximum aversions seen with naloxone in the drug-naive animal under the same training conditions. Thus, the data from the present study confirmed the notion that low doses of PTZ and VPA in the naive animal may activate processes activated by drug withdrawal, including those important for the motivational effect of withdrawal. However, it was also pointed out that the lowest dose VPA producing aversion was higher than that found here to produce writhes and ataxia (80 mg/kg) but the same as that required for shaking (160 mg/kg), while the PTZ aversion was at a dose lower than that known to produce a PTZ cue. Implications were discussed for using withdrawal-like phenomena as a model in the non-treated organism of clinically-relevant withdrawal effects.
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PMID:Withdrawal-like effects of pentylenetetrazol and valproate in the naive organism: a model of motivation produced by opiate withdrawal? 758 68

The anticonvulsant properties of F-721 (3-diethylamino-2,2-dimethylpropyl-5-[p-trifluoromethylphenyl]-2-f uroate hydrochloride) were investigated in a battery of in vivo and in vitro anticonvulsant model systems. After intraperitoneal (ip) administration in mice, F-721 was effective in nontoxic doses against maximal electroshock (MES), subcutaneous picrotoxin clonic, intracerebroventricular (icv) N-methyl-D-aspartate (NMDA) tonic, icv NMDA clonic and icv quisqualic acid tonic seizures (ED50s: 11.1, 28.4, 1.76, 3.4, and 4.4 mg/kg, respectively). F-721 exhibited only partial activity against clonic seizures induced in the subcutaneous Metrazol and subcutaneous bicuculline test in mice and was inactive in this species against tonic seizures induced in the subcutaneous strychnine test. F-721 was effective against MES seizures following oral administration to mice (ED50: 31.3 mg/kg) and only partially effective by this route against clonic seizures induced by subcutaneous Metrazol. In rats, F-721 was a potent anticonvulsant in the maximal electroshock model following oral administration (ED50: 9.9 mg/kg). F-721 was also effective against corneal-kindled and amygdaloid-kindled seizures in rats. F-721 suppressed stage 5 seizures in corneal-kindled rats with an ED50 of 15 mg/kg, ip. In addition, it also decreased the afterdischarge duration and behavioral seizure stage in amygdaloid-kindled rats at doses that did not cause sedation or ataxia. At 40 mg/kg, F-721 reduced afterdischarge duration by 83.2% and reduced the seizure severity score to 1.7. The ED50 for 50% reduction of afterdischarge duration was 16.3 mg/kg, ip. In cultured mouse spinal cord neurons, F-721 suppressed sustained repetitive firing in response to a depolarizing current with a median inhibitory concentration (IC50) of 1.9 microM. F-721 had no effect on adenosine uptake, gamma-aminobutyric acid or NMDA receptor binding. Comparative data from previous studies with clinically established antiepileptic agents reveal that F-721's profile of activity most closely resembles that of phenytoin and carbamazepine. However, F-721 was notably more efficacious in suppressing amygdaloid-kindled seizures in rats and was a more potent antagonist of icv NMDA clonic seizures. Our studies indicate that F-721 is a potent, orally active anticonvulsant with a favorable margin of safety. The profile of anticonvulsant activity of F-721 suggests potential utility in the management of generalized tonic-clonic, simple and complex partial seizures.
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PMID:Characterization of the anticonvulsant properties of F-721. 839 82


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